Protectant for UV-induced skin damage

ABSTRACT

The present invention provides a method for protecting against UV radiation-induced skin damage. Specifically, compositions including dapsone are administered to provide UV protection. The dapsone compositions may be administered orally, or by other parenteral routes, such as topically, transdermally, by inhalation, and the like.

FIELD OF THE INVENTION

[0001] The present invention relates to the field of dermatologicpharmacology. In particular, UV protectants that reduce the risk of skindamage are described. The compositions are formulated with dapsone asthe active protective ingredient.

BACKGROUND OF THE INVENTION

[0002] Human skin is a primary target of nonionizing electromagneticradiation in the ultraviolet, visible, and infrared ranges, and consistsof three distinct layers: the stratum corneum, the epidermis, and thedermis. The epidermis and dermis contain several molecules known aschromophores, that are capable of absorbing light or UV radiation (UVR).The main chromophores in human skin include such molecules as nucleicacids, aromatic amino acids, proteins, porphyrins, carotenoids,steroids, and quinones (Mary S. Matsui and Vincent A. DeLeo, SkinCancer: Mechanisms and Human Relevance Chp. 4, 22 (Hasan Mukhtar ed.,1995)).

[0003] The UV spectrum is divided into A, B, and C ranges. The UVC rangeextends from wavelengths between 200 and 290 nm. The UVB spectrumincludes wavelengths between 290 and 320 nm, and is generally known asthe sunburn spectrum because it produces erythema in human skin. UVAradiation includes wavelengths between 320 to 400 nm. Atmospheric ozoneabsorbs all UVC and much of the UVB, so that the spectrum of UVradiation at the earth's surface consists primarily of UVA. The depth towhich a photon penetrates in vivo is related to its wavelength. Thus,most UVB radiation transmitted through the ozone layer is absorbedwithin the first 0.03 mm of the epidermis, whereas one third of UVAradiation penetrates to a depth of 0.1 mm (Hardie et al., Surgery 87:177(1980)).

[0004] When the skin is exposed to UVR, energy transferred tochromophores from the absorbed radiation may result in molecularreorganization and/or interaction with nearby biomolecules. For example,after UVR absorption, DNA may form dipyrimidine lesions, such ascyclobutane pyrimidine dimers. In turn, characteristic mutations result,e.g., mutations in p53, that have been shown to be important inproducing non-melanoma skin cancer. (A. Ziegler et al., Nature372:773-776 (1994)). Furthermore, the UV-induced conversion of urocanicacid from the trans to cis isomer has been linked to the subsequentdevelopment of non-melanoma skin cancers (Craig A. Elmets et al., SkinCancer: Mechanisms and Human Relevance Chp. 18, 230 (Hasan Mukhtar ed.,1995)).

[0005] Further insight into UV-induced skin tumor formation has beengained from studies in rodents. UV-induced skin tumors stimulate astrong immune response. If UV-induced tumors are implanted into normal,genetically identical mice, they are promptly rejected by the hostimmune-system and the animals survive. If the same tumor is implantedinto mice that have been exposed to subcarcinogenic doses of UVR,immunological destruction of the tumor does not occur. These resultsindicate that UVR produces mutations in skin cells and facilitates tumorgrowth by impairing immune surveillance. The presence of bothdeficiencies is necessary for clinically apparent skin cancers todevelop (J. T. Krutmann and C. A. Elmets eds. (1995). Photoimmunology.Oxford: Blackwell Scientific).

[0006] Currently marketed sunscreens function either as ultraviolet (UV)filters or UV blocks. UV blocks, such as TiO₂ and ZnO, as well asderivatives of other metal-oxides, form a physical barrier that scattersUV light. These UV blocks offer the most comprehensive sunscreenprotection, blocking the full spectrum of UVA and UVB light. However,the most commonly used sunscreens are UV filters, which are typicallyorganic compounds. A disadvantage of UV filters is that each organiccompound has a limited range of maximum UV absorptivity, rendering eachreagent better suited for either UVA protection or UVB protection, butnot both.

[0007] The UV-induced mouse tumor model has proven very useful not onlyin gaining mechanistic understanding of skin tumor formation, but alsoin determining if topical products promote or inhibit the formation ofUV-induced tumors. A standard UV carcinogenicity model accepted for thetesting of topical pharmaceuticals employs the albino hairlessCrl:SKH1-hr BR mouse (P. D. Forbes et al., Photobiology. 663-669 (E.Riklis ed., 1991)).

[0008] After administration of a topical formulation, experimentalprotocols typically instruct that mice be irradiated once daily, fivedays per week, for 40 weeks. Intensity and cumulative UV radiation doseis measured in Robertson-Bergen Units (RBU). The RBU is a measure ofbiological effectiveness for UVR, with 400 RBU being approximately oneminimal erythema dose in previously untanned human skin, i.e., about 30mJ/cm² in a sun-sensitive skin type I or II. Mouse carcinogenicitystudies are completed at 600 RBU per week because this produces anappropriate tumor mean latent period for comparison with test articletreated and untreated controls. At this radiation level, about half ofthe untreated animals will have a first perceptible tumor by weekforty-one. A higher control UVR level of 1200 RBU per week results in asignificant reduction in the median tumor latent period. At thisradiation dose, about half of the untreated animals will have a firstperceptible tumor by week twenty-four. Animals continue to be observedfor 12 weeks after 40 weeks of product application to provide a total of52 weeks of tumor data.

[0009] At least two common topical therapies promote tumor formation inthis UV induced mouse carcinogenicity model. Benzoyl peroxide andretinoids such as tretinoin, which are commonly used to treat acne,promote the formation of skin tumors compared to untreated or vehiclecontrols. (Physicians Desk Reference, 56^(th) Edition, Medical EconomicsCompany, Inc., Montvale N.J., (2002)). While many topical productscontaining these actives are currently in use, the patients who use themare strongly encouraged to avoid sun exposure on their face after usingthe product. However, significantly shielding the face from sunexposure, especially for young adults, is virtually impossible forproducts that are often used twice daily.

[0010] U.S. Pat. No. 6,113,888 to Castro et al.; U.S. Pat. No. 6,200,964to Singleton et al.; and U.S. Pat. No. 6,231,837 to Stroud et al.describe topical compositions that contain therapeutics. However, thetherapeutic is not included to provide protection from ultravioletradiation. If UVR protection is desired, sunscreens are added to theformulations.

[0011] Topical compositions including dapsone have been described inU.S. Pat. Nos. 5,863,560 and 6,060,085 to Osborne, and U.S. applicationSer. No. 10/081,050 to Osborne, which are herein incorporated byreference in their entirety. However, these compositions were formulatedto treat acne, not to prevent skin damage from UV radiation.

[0012] Therefore, new compositions that protect against UV-induced skindamage are needed.

SUMMARY OF THE INVENTION

[0013] The present invention is a method for protecting against UVradiation-induced skin damage in individuals by selecting individuals inneed of protection from UV radiation and administering to them acomposition that includes dapsone. In general, selection of theindividual in need of protection from UV radiation is based upon factorssuch as the frequency and duration of UV radiation exposure, e.g., sunexposure, and/or the risk of the individual for UV-induced skin damage.In turn, the risk is typically assessed by examining such factors as theindividual's age and predisposition to sunburn or develop pigmentedlesions after sun exposure, any genetic predisposition to skin cancer,prior medical history of UV-induced skin damage, and presentation ofUV-induced skin damage at the time of examination.

[0014] The dapsone compositions may be provided in formulationsincluding, but not limited to, gels, creams, lotions, solutions,hydrophilic or hydrophobic ointments, microemulsions, shake-powders,aerosol and pump sprays, tablets, capsules, patches, films, andsuppositories. The dapsone used in the compositions may be in dissolvedor particulate form, or a mixture of dissolved and microparticulatedapsone. The composition that is administered may also include additivessuch as preservatives, antioxidants, fragrances, or colorants.

[0015] Besides protecting against signs of aging (e.g., wrinkles) andhyperpigmentation, compositions including dapsone may be administered toprotect against the formation, in other words, prevent the developmentof, UV-induced premalignant skin lesions such as actinic keratosis, aswell as UV-induced malignant tumors of the skin. In another embodiment,the dapsone compositions may be administered to individuals having atleast one premalignant skin lesion to prevent the premalignant skinlesion from becoming a malignant skin tumor.

BRIEF DESCRIPTION OF THE DRAWINGS

[0016]FIG. 1 shows a decrease in prevalence of tumor formation in albinohairless mice exposed to UVR at 600 and 1200 RBU with the use of varioustopical dapsone compositions.

DETAILED DESCRIPTION OF THE INVENTION

[0017] The inventive methods provide dapsone compositions that protectagainst ultraviolet radiation-induced skin damage.

[0018] As used herein, the terms “UV-induced skin damage” or “UV-inducedskin disorder” do not refer to acne. These terms are usedinterchangeably and refer to skin damage resulting from exposure toultraviolet light in the A (320-400 nm), B (290-320 nm), or C ranges(200-290 nm). Examples of UV-induced skin damage, also referred toherein as “skin lesions”, include wrinkles, hyperpigmentation,dysplasias such as actinic keratosis, and malignant skin tumors such assquamous cell or basal cell carcimona.

[0019] As used herein, the term “protects” or “protecting” refers to areduction in the amount of skin damage which can be manifested, e.g., bya decrease in the number and/or severity of individual skin lesions, orprevention of the development of skin lesions.

[0020] The term “topical” as used herein refers to the route ofadministration of a composition that involves direct application to thebody part being treated, e.g., the skin for dermatological compositions.Examples of topical application include application to the skin of gelsor other semisolids to rub-on, solutions to spray, or liquids to beapplied by an applicator. Rinse-off application with washes, cleansers,or shampoos are also examples of topical application. Typically, areasof the body suitable for application of compositions having dapsoneinclude the skin of the face, throat, neck, scalp, chest, back, ears,and other skin sites where sun exposure may occur.

[0021] By use of the term “dapsone” it is meant the chemical compounddapsone having the chemical formula C₁₂H₁₂N₂O₂S as well asbis(4-aminophenyl)sulfone, 4′,4′-diaminodiphenyl sulfone and itshydrates, 4,4′-sulfonylbisbenzeneamine, 4,4′-sulfonyldianiline,diaphenylsulfone, dapsone analogs, and dapsone related compounds.“Dapsone analogs” refers to chemical compounds that have similarchemical structures and thus similar therapeutic potential to dapsonesuch as the substituted bis(4-aminophenyl)-sulfones. “Dapsone relatedcompounds” refers to chemical compounds that have similar therapeuticactivity, but are not as closely related by chemical structure todapsone such as the substituted 2,4-diamino-5-benzylpyrimidines.

Dapsone Compositions

[0022] Dapsone Topical Gel

[0023] The topical gel compositions of this invention utilize variousforms of dapsone. For instance, in one embodiment, dapsone may bepresent in the composition as only dissolved dapsone. In anotherembodiment, dapsone may be present in the composition only asmicroparticulate dapsone. In a further embodiment, the dermatologicalcomposition exhibits an optimal balance between dissolved dapsone thatis available to cross through the stratum corneum to become systemicallyavailable, and microparticulate dapsone that is retained in or above thestratum corneum to serve as a reservoir or to provide dapsone to thesupracorneum zone. The microparticulate dapsone may comprise acrystalline precipitant or an amorphous precipitant.

[0024] In one embodiment, the dermatological composition that is appliedcomprises a semi-solid or gel-like vehicle that may include a polymerthickener, water, preservatives, active surfactants or emulsifiers,antioxidants, sunscreens, and a solvent or mixed solvent system. Thesolvent or mixed solvent system is important to the formation of themicroparticulate to dissolved dapsone ratio. The formation of themicroparticulate, however, should not interfere with the ability of thepolymer thickener or preservative systems to perform their functions.

[0025] Polymer thickeners that may be used include those known to oneskilled in the art, such as hydrophilic and hydroalcoholic gellingagents frequently used in the cosmetic and pharmaceutical industries.Preferably, the hydrophilic or hydroalcoholic gelling agent comprises“CARBOPOL®” (B. F. Goodrich, Cleveland, Ohio), “HYPAN®” (KingstonTechnologies, Dayton, N.J.), “NATROSOL®” (Aqualon, Wilmington, Del.),“KLUCEL®” (Aqualon, Wilmington, Del.), or “STABILEZE®” (ISPTechnologies, Wayne, N.J.). Preferably, the gelling agent comprisesbetween about 0.2% to about 4% by weight of the composition. Moreparticularly, the preferred compositional weight percent range for“CARBOPOL®” is between about 0.5% to about 2%, while the preferredweight percent range for “NATROSOL® and “KLUCEL®” is between about 0.5%to about 4%. The preferred compositional weight percent range for both“HYPAN®” and “STABILEZE®” is between about 0.5% to about 4%.

[0026] “CARBOPOL®” is one of numerous cross-linked acrylic acid polymersthat are given the general adopted name carbomer. These polymersdissolve in water and form a clear or slightly hazy gel uponneutralization with a base such as sodium hydroxide, potassiumhydroxide, triethanolamine, or other amine bases. “KLUCEL®” is acellulose polymer that is dispersed in water and forms a uniform gelupon complete hydration. Other preferred gelling polymers includehydroxyethylcellulose, hydroxypropylcellulose, cellulose gum, MVA/MAcopolymers, MVE/MA decadiene crosspolymer, PVM/MA copolymer, or acombination thereof.

[0027] Preservatives may also be used in this dermatological compositionand preferably comprise about 0.05% to 0.5% by weight of the totalcomposition. The use of preservatives assures that if the product ismicrobially contaminated, the formulation will prevent or diminishmicroorganism growth. Some preservatives useful in this inventioninclude methylparaben, propylparaben, butylparaben, chloroxylenol,sodium benzoate, DMDM Hydantoin, 3-Iodo-2-Propylbutyl carbamate,potassium sorbate, chlorhexidine digluconate, or a combination thereof.

[0028] In one embodiment, the dermatological composition that is appliedincludes 0.5% to 4.0% carbomer and about 0.5% to 10% dapsone that existsin both a dissolved state and a microparticulate state. In anotherembodiment, the dermatological composition comprises about 1% carbomer,about 80-90% water, about 10% (diethylene glycol monoethyl ether (DGME),about 0.2% methylparaben, and about 0.3% to 3.0% dapsone including bothmicroparticulate dapsone and dissolved dapsone, and about 2% of a base.More particularly, the carbomer may include “CARBOPOL® 980” and the basemay include sodium hydroxide solution.

[0029] In a another embodiment, the composition comprises dapsone andethoxydiglycol, which allows for an optimized ratio of microparticulatedrug to dissolved drug. This ratio determines the amount of drugdelivered, compared to the amount of drug retained in or above thestratum corneum to function in the supracorneum domain. The system ofdapsone and DGME may include purified water combined with “CARBOPOL®”gelling polymer, methylparaben, propylparaben, titanium dioxide, BHA,and a base to neutralize the “CARBOPOL®.”

[0030] Dapsone Topical Cream or Lotion

[0031] In another embodiment, dapsone may be applied as a topical creamor lotion in which dapsone may be dissolved or dispersed or bothpartially dissolved and partially dispersed. Topical creams or lotionsmay be either oil-in-water emulsions or water-in-oil emulsions. The oilphase may include but is not limited to fatty alcohols, acids, or esterssuch as cetyl palmitate, cetyl alcohol, stearyl alcohol, stearic acid,isopropyl stearate, glycerol stearate, mineral oil, white petrolatum, orother oils alone or in combination. The topical creams or lotions may beformulated for use as sunscreens.

[0032] Emulsifiers that may be added to the composition include, but arenot limited to, steareth 20, ceteth 20, sorbitan sesquioleate, sorbitanmono-oleate, propylene glycol stearate, dosium lauroyl sarcosinate,polysorbate 60, or combination. Preservatives, antioxidants, fragrances,colorants, thickeners, and other additives required to achieve apharmaceutically or cosmetically acceptable or preferred product mayalso be included. However, topical creams and lotions are not limited tothese components since one skilled in the art will be aware ofadditional components useful in the formulation of topical creams andlotions.

[0033] Dapsone Topical Solution or Suspension

[0034] In another embodiment, dapsone may be applied as a solution orsuspension. These are fluid solvent or mixed-solvent systems including,but not limited to, water, ethanol, propylene glycol, glycerol,polyethylene glycol, ethyl acetate, propylene carbonate, n-methylpyrrolidone, triethanolamine, 1, 4-butanediol, triacetin, diacetin,dimethyl isosorbide alone or in combination. Preservatives,antioxidants, fragrances, colorants, thickeners, suspending agents,enhancers, and other additives required to achieve pharmaceutically orcosmetically acceptable or preferred product may also be included.Again, topical solutions or suspensions are not limited to thesecomponents, since one skilled in the art will be aware of additionalcomponents useful in the formulation of topical solutions orsuspensions.

[0035] Additional Dapsone Formulations

[0036] Dapsone may also be topically applied using a pharmaceutical orcosmetic carrier form such as a hydrophobic or hydrophilic ointment,roll-on or stick product, microemulsion, shake powder, an aerosolizedspray or mousse, a pump spray or mousse, or bath additive. Examples ofointments include essentially non-aqueous mixtures of petrolatum,lanolin, polyethylene glycol, plant or animal oils, either hydrogenatedor otherwise chemically modified. An ointment may also contain a solventin which dapsone is either fully or partially dissolved. Additionalpharmaceutical carriers will be known to those skilled in the art andthis list should not be considered to be limiting.

[0037] In addition to topical compositions, dapsone may be formulated aspharmaceutical preparations including, but not limited to, granules,tablets, suppositories, capsules, suspensions, patches, films, andaerosols. Pharmaceutical grade organic or inorganic carriers and/ordiluents suitable for inhalation or oral, parenteral, transmucosal, ortransdermal administration may be used to formulate compositionsincluding dapsone. Stabilizing agents, wetting and emulsifying agents,salts for varying the osmotic pressure, or buffers for securing anadequate pH value may also be included in the dapsone compositions.

Administration of Dapsone Compositions

[0038] In addition to topical administration, dapsone, dapsone analogs,or dapsone related compounds may have sufficient partitioning to theskin or sufficient activity in the skin to be delivered by other routesof administration. For example, systemic dosing may accompany topicaldosing, or systemic dosing for the purpose of photoprotection may beused as a singular therapy. Other routes and methods of administrationwill be known to those skilled in the art. These include, but are notlimited to, oral, rectal, vaginal, nasal, ocular, oral transmucosal andother transmucosal, transdermal, parenteral, and pulmonary routes.Parenteral administration includes, without limitation, intravenous,subcutaneous, intramuscular, intra-arterial, intrathecal, andintraperitoneal administration. Pulmonary delivery may be achieved bynebulization, aerosol inhalation, or dry powder inhalation. Productsdeveloped for administration using these alternate delivery routes willhave compositions recognized by those skilled in the art, as describedin Remington: The Science and Practice of Pharmacy, 19^(th) Edition,Mack Publishing Company, Easton Pa., (1995).

[0039] In one variation, the dapsone compositions are administered toprotect individuals against UV-induced skin damage such as sunburn,malignant skin tumors, premalignant lesions, and wrinkles. Typically,the dapsone compositions are administered once daily, but may beadministered more frequently if desired. In another variation, thedapsone compositions are administered to prevent premalignant skinlesions from progressing to malignant skin tumors in individuals.

[0040] The dapsone compositions are administered to selectedindividuals. By “selected” it is meant individuals in whom UV protectionis considered desirable because of age, frequent or long duration ofexposure to UV radiation, e.g., sun, and/or because they possess anincreased risk for UV radiation-induced skin damage. For example,individuals at increased risk are those who are more prone to sunburn ordevelop pigmented lesions after sun exposure, or who due to geneticmakeup, have a condition that predisposes them to skin cancer, e.g.,xeroderma pigmentosum. Furthermore, individuals with a prior medicalhistory of a UV-induced skin disorder or who present with UV-inducedskin damage at the time the need for UV protection is determined are atincreased risk.

[0041] The dapsone compositions are typically administered before theindividual engages in an activity that involves UV radiation exposure.The activity may be an outdoor activity such as sunbathing, walking,running, swimming, biking, and the like, engaged in for purposes ofrecreation or physical fitness. The dapsone compositions may also beadministered to individuals engaging in indoor activities, e.g., indoortanning or laboratory work that involves exposure to ultraviolet light.

Method for Preparing the Daspsone Dermatological Composition

[0042] In general, the method for producing a dermatological gelcomposition having dissolved dapsone and microparticulate dapsoneprecipitates comprises the steps of completely dissolving dapsone in asolvent or solvent mixture; adding and adequately dispersing a polymericthickener in water; and combining the dissolved dapsone with thedispersed polymeric thickener. Alternatively, water may be slowly addedto the dissolved dapsone, followed by the addition of a polymericthickener. Ethoxydigylcol and 1-methyl-2-pyrollidone are preferredsolvents for use in the topically applied dermatological composition.

[0043] In one embodiment, the method for preparing a topically applieddermatological composition having dissolved and microparticulate dapsonecomprises the steps of forming a homogenous dispersion by stirringpurified water vigorously enough to form a vortex and sifting gelpolymer into the vortex formed in the water while continuing to stir;forming a pharmaceutical component by dissolving methyl paraben andpropylparaben in DGME by mixing to form a solution, and mixing dapsonewith the solution until the pharmaceutical is dissolved; mixing thepharmaceutical component with the homogenous dispersion to form amicroparticulate dapsone dispersion; and adding a caustic material.

[0044] In another embodiment, the method for preparing a topicallyapplied dermatological composition having only dissolved dapsoneincludes the steps of dissolving dapsone in an oil phase or mixedsolvent system. The dissolved dapsone is then combined with the waterphase of an emulsion or thickeners or other cosmetic or pharmaceuticalexcipients to form a dermatological product. This topical cream, lotion,solution, ointment or other topical formulation will contain onlydissolved dapsone at ambient conditions.

[0045] In yet another embodiment, the method for preparing a topicallyapplied dermatological composition having primarily dispersed dapsoneincludes the step of dispersing dapsone in a water phase, non-solvatingsolvent or mixed solvent system. The dispersed dapsone is then combinedwith the oil phase of an emulsion or thickeners or other cosmetic orpharmaceutical excipients to form a dermatological product. This topicalcream, lotion, suspension, ointment or other topical formulation willcontain dispersed dapsone particles and minimal (less than about 5%)dissolved dapsone at ambient conditions.

[0046] The order in which reagents are combined may be important,depending on the particular reagents necessary for the target mixture.For example, after a pharmaceutical such as dapsone is dissolved in asolvent such as DGME, water may be slowly added to the dapsone in theDGME solution, or the dapsone in DGME solution may be added to the waterwith mixing. Adding the dapsone in DGME solution to water may result inless polydispersity in the size of the microparticulates than addingwater to the dapsone in DGME solutions. The carbomer is generallydispersed in the water component of the formulation, while the remainingingredients will be dissolved or dispersed in whichever of the twocomponents are best for dissolving or dispersing the ingredient. Forexample, it is suggested to dissolve methylparaben, propylparaben, andBHA in DGME. After the DGME component and water component are combined,neutralizer is added to formulate the gel.

EXAMPLES

[0047] The following example is provided to show that dapsone has anunexpected protective benefit in the treatment of ultravioletradiation-induced skin tumors.

[0048] Those skilled in the art will recognize that while specificembodiments have been illustrated and described, various modificationsand changes may be made without it departing from the spirit and scopeof the invention.

Example 1 Effect of Dapsone on Skin Tumor Formation in Mice

[0049] Example 1 demonstrates the protective effect of dapsone onUV-induced skin tumor formation. Male and female albino hairlessCrl:SKH1-hrBR mice (36/sex/group) were obtained from Charles RiverLaboratories (Wilmington, Mass.) and individually housed incustom-designed stainless steel irradiation cages.

[0050] The experimental dapsone formulations (50 μl/mouse, Mondaythrough Friday) were administered to the dorsum and sides of the mice toan area of approximately 25 cm² using a glass rod, and the miceirradiated once daily, 5 days per week, for 40 weeks. Aqueous carbomergels containing 1% dapsone/10% DGME (diethylene glycol monoethyl ether);3% dapsone/17.5% DGME; or 5% dapsone/25% DGME were chosen fromrange-finding studies. A vehicle control aqueous carbomer gel contained25% DGME. Formulations were administered one hour before irradiation onMonday, Wednesday, and Friday and one hour after irradiation on Tuesdayand Thursday. Mice were then maintained without being dosed for anadditional 12 weeks for a total of 52 weeks.

[0051] The simulated solar radiation (SSR) source was a 6.5 kilowattzenon long arc water-cooled burner, filtered by a 1 mm thick Schott WG320 doped glass filter. During exposure the mice were continuouslymonitored by a customized detector, which records both intensity andcumulative UVR dose in Robertson-Berger Units (RBU, 400 RBU approximatesone minimal erythema dose (MED) in previously untanned human skin). Thelow UVR calibration group (120 RBU/daily, 600 RBU/week) produced anappropriate tumor median latent period for comparison with other groups.The high UVR calibration group (240 RBU/day, 1200 RBU/week) produced asignificant decrease in median tumor latent period. The test level ofUVR (600 RBU per week) permits detection of a modified photocarcinogenicresponse by the test system in response to a test article. Over thecourse of the study, the daily UVR dose was consistent and the totaldose across groups was appropriate.

[0052] All mice were observed for viability at least twice daily, andweekly for general skin observations. Other clinical observations wererecorded weekly; body weights were recorded weekly for the first 13weeks, and then every four weeks thereafter and at sacrifice. IndividualUV-induced skin tumor data (size and location) were electronicallyrecorded. Any mouse bearing a tumor>10 mm planar diameter wassacrificed. Furthermore, all mice in a group were sacrificed when:

[0053] 1) fewer than 50% of the mice per sex survived;

[0054] 2) more than 50% of the surviving mice in the group had tumors ofat least 4 mm (planar diameter); and

[0055] 3) the Study Director reviewed the data and approved thesacrifice.

[0056] Tables, graphs, and statistical testing of tumor data wereprovided as output from the ROELEE program (P. N. Lee Statistics andComputing, Ltd., Sutton, United Kingdom). Group comparisons of tumorprevalence were based on the methods described by Peto and colleagues(Peto, R., et. al. (1980). Guidelines for Simple, Sensitive SignificanceTests for Carcinogenic Effects in Long-Term Animal Experiments. IARCMonographs, Supplement 2. Long-Term and Short-Term Screening Assays forCarcinogens: A Critical Appraisal).

[0057] Since bi-directional effects on carcinogenicity are plausible,testing was based on two-tailed probabilities (i.e., the null hypothesisstates that the superimposed variable does not alter carcinogenicity).Evaluations were based on two-group comparisons. Statisticalinterpretation was based primarily on tumors at least 1 mm in diameterusing the following descriptive parameters:

[0058] 1) “Median Onset” or “Median Week to Tumor”: The time at whichone-half of the members of other groups have acquired one or morequalifying tumors, and the associated 95% confidence interval. Separateestimates evaluated “biased” medians (based on survivors) andmortality-adjusted medians.

[0059] 2. “Mortality-Free Prevalence”: The proportion of mice in a groupexhibiting one or more qualifying tumors, as a function of time, andadjusted for the effects of competing mortality. This descriptor is thecomplementary probability to the Kaplan-Meier “probability of survivalwithout a tumor” and is derived form calculations of the Kaplan-Meiertype (Kaplan, E. L., and Meier, P. J. Am. Stat. Assoc. 53:457-481(1958)).

[0060] 3. “Tumor Yield”: The number of tumors present, divided by thenumber of surviving mice (i.e., average number of tumors per mouse).

[0061] 4. “Survival”: The absolute number of mice alive at the time ofobservation, compared to the initial number in each group.

[0062] Table 1 shows that the Unbiased Median Weeks to Tumor wasunaffected by the vehicle formulation (25% DGME vehicle), and delayed ingroups administered the dapsone formulations and exposed to 600RBU/week. The group exposed to high UVR (1200 RBU/week), served as apositive control to show that the Unbiased Median Weeks to Tumor wasaccelerated. The unbiased median latent period was not achieved by theend of the study for the 3% dapsone/17.5% DGME gel group, or for the 5%dapsone/25% DGME gel group for male mice. An entry of 53 weeks is usedin Table 1 to illustrate this fact. Dapsone increased the UnbiasedMedian Weeks to Tumor in a dose-dependent manner, indicating a reductionin the photocarcinogenic response of the mice to UVR in these groups.

[0063]FIG. 1 shows the prevalence by week of the first 1 mm tumor forthe sexes combined. In comparison with the 25% DGME vehicle formulationadministration (line 1), all dapsone containing gels (line 2, 1% dapsonegel; line 3, 3% dapsone gel; line 4, 5% dapsone gel) significantlyreduced the development of skin tumors in mice exposed to 600 RBU/weekfor the sexes combined (p<0.001 for 1%, 3%, and 5% dapsone gel), in malemice (data not shown, p<0.01 for 1% dapsone gel, and p<0.001 for 3%dapsone gel, and<0.001 for 5% dapsone gel), and in female mice (data notshown, p<0.01 for 1% and 3% dapsone gel and p<0.001 for 5% dapsone gel).The prevalence of 1 mm tumor formation in untreated mice exposed to 600RBU/week (line 5) paralleled that of mice administered the 25% DGMEvehicle formulation (line 1). Line 6 demonstrates the increase in skintumor formation in untreated mice exposed to 1200 RBU/week.

[0064] The Tumor Potency Ratio (TPR) expresses the influence of a testarticle on the skin's response to UVR exposure. The concept of TPRdepends on the relationship between the weekly UVR dose, as a measure ofstimulus rate, and the chosen response measure of Unbiased Median Weekto Tumor for each group (tumors>1 mm). With those values and the doserate calibration for the untreated 600 RBU/week and 1200 RBU/weekgroups, the apparent radiation dose rate of the groups was calculated.The difference from the nominal rate represents the effect of a testvariable on UVR dose delivery. Since unbiased median latent period wasnot achieved by the end of the study (52 weeks) for the 3% dapsone gelgroup, or the 5% dapsone gel group for males, the estimated TPR wascalculated from the estimated unbiased median latent period of 53 Asshown in Table 2, the TPR was reduced with dapsone application in adose-dependent manner in sexes combined, indicating a dose-dependentinhibitory effect on UVR-induced skin tumor production. The vehicleformulation had no effect on TPR.

[0065] Furthermore, biologically important and/or statisticallysignificant reductions occurred in erythema, edema, flaking and/orthickening in the groups of male and/or female mice administered dapsoneformulations (data not shown).

[0066] In sum, the administration of the vehicle or dapsone formulationsdid not enhance photocarcinogenesis; rather, the dapsone formulationsprotected against UV radiation-induced skin tumor development. Thisconclusion is supported by the tumor endpoints Unbiased Median Weeks toTumor, Peto Analysis of Tumor Onset, Prevalence Curves, Tumor Yield perSurvivor and Tumor Potency Ratio. These observations also suggest areduction in the UV radiation-induced inflammatory process in the groupsadministered the dapsone formulations.

[0067] All publications and patent applications cited in thisapplication are herein incorporated by reference in their entirety.Although the foregoing invention has been described by way ofillustration and example for purposes of clarity and understanding, itwill be readily apparent to those of ordinary skill in the art in lightof the teachings of this invention that certain changes andmodifications may be made thereto without departing from the spirit orscope of the appended claims. TABLE 1 Unbiased Median Weeks to Tumor forTumors ≧ 1 mm 25% 1% Dapsone 3% Dapsone 5% Dapsone DGME in a 10% in a17.5% in a 25% Formulation Vehicle DGME Gel DGME Gel DGME Gel None NoneUVR Exposure RBU/Week 600 600 600 600 600 1200 Sexes Combined (weeks)41.5 47.50 48.00 49.00 41.50 24.50 Males (weeks) 45.25 50.00 53.00 53.0044.00 25.00 Females Median (weeks) 39.50 45.00 45.50 49.00 39.50 24.00

[0068] TABLE 2 Tumor Potency Ratios ( ≧1 mm Tumor Size) 25% 1% Dapsone3% Dapsone 5% Dapsone DGME in a 10% in a 17.5% in a 25% FormulationVehicle DGME Gel DGME Gel DGME Gel None None UVR Exposure RBU/Week 600600 600 600 600 1200 Sexes Combined 1.00 0.84 0.83 0.80 1 2 Males 1.060.97 0.85 0.80 1 2 Females Median 1.00 0.86 0.82 0.74 1 2

1. A method for protecting against ultraviolet radiation-induced skindamage in an individual comprising: a) selecting an individual in needof protection from ultraviolet radiation; and b) administering acomposition to the individual, wherein said composition comprisesdapsone.
 2. The method of claim 1 wherein said individual is in need ofprotection from a malignant skin tumor.
 3. The method of claim 2 whereinsaid individual is in need of protection from squamous cell carcinoma.4. The method of claim 2 wherein said individual is in need ofprotection from basal cell carcinoma.
 5. The method of claim 1 whereinsaid individual is in need of protection from a premalignant skinlesion.
 6. The method of claim 5 wherein said individual is in need ofprotection from actinic keratosis.
 7. The method of claim 1 wherein saidcomposition is administered before said individual engages in anactivity, wherein said activity exposes said individual to ultravioletradiation.
 8. The method of claim 7 wherein said activity is an outdooractivity.
 9. The method of claim 8 wherein said activity is sunbathing.10. The method of claim 8 wherein said activity is swimming.
 11. Themethod of claim 8 wherein said activity is running.
 12. The method ofclaim 7 wherein said activity is an indoor activity.
 13. The method ofclaim 12 wherein said activity is tanning.
 14. The method of claim 1wherein said composition is administered topically.
 15. The method ofclaim 14 wherein said composition is a semi-solid aqueous gel.
 16. Themethod of claim 14 wherein said composition is a cream.
 17. The methodof claim 14 wherein said composition is a lotion.
 18. The method ofclaim 14 wherein said composition is a solution.
 19. The method of claim14 wherein said composition is an ointment.
 20. The method of claim 14wherein said composition is a spray.
 21. The method of claim 1 whereinsaid composition is orally administered.
 22. The method of claim 1wherein said composition is parenterally administered.
 23. The method ofclaim 1 wherein said composition is transmucosally administered.
 24. Themethod of claim 1 wherein said composition is transdermallyadministered.
 25. The method of claim 1 wherein said composition isadministered by inhalation.
 26. The method of claim 1 wherein saidcomposition further comprises an additive selected from the groupconsisting of a preservative, an antioxidant, a fragrance, and acolorant.
 27. The method of claim 1 wherein said composition comprisesat least about 1% dapsone.
 28. The method of claim 1 wherein saidcomposition comprises at least about 3% dapsone.
 29. The method of claim1 wherein said composition comprises at least about 5% dapsone.
 30. Amethod for preventing a premalignant skin lesion from becoming amalignant skin tumor comprising administering a composition to anindividual having at least one premalignant skin lesion, wherein saidcomposition comprises dapsone.
 31. A method for preventing UV-inducedmalignant skin tumor formation in an individual comprising: a) selectingthe individual in need of protection from UV radiation; and b)administering a composition to the individual, wherein said compositioncomprises dapsone.